This K02 Award will fund the salary support for all of Dr. Roth's research related activities. Three major goals are proposed for this funding cycle including: (1) Characterization of the structure and function of 5-HT2-family serotonin receptors; (2) Discovering the cellular and molecular mechanisms responsible for the regulation of 5-HT2A receptors and (3) Administering the National Institute of Mental Health Psychoactive Drug Screening Program. Characterizing the structure and function of 5-HT2A receptors is of great importance for mental health-related research because a number of psychoactive compounds including atypical antipsychotic drugs, antidepressants and some anxiolytic medications exert their actions via interacting with 5-HT2A receptors. Understanding how such drugs interact with 5-HT2-family receptors at the atomic level may lead to novel insights into drug design and development. Discovering how the 5-HT2A receptor is regulated is important for understanding the pharmacological mechanisms by which drugs may regulate neurotransmitter receptor levels. 5-HT2A receptors are regulated in a paradoxical manner by antagonists and insights into the cellular and molecular mechanisms by which these alterations occur could be of importance for understanding 6-protein receptor coupled regulation. Finally, the NIMH Psychoactive Drug Screening Program is responsible for characterizing the pharmacology of novel psychoactive compounds, some of which may represent new therapeutic agents. A full molecular pharmacologic characterization of these compounds is essential prior to their use in humans.